1. Field of the invention
This invention relates to derivatives of tamoxifen, their preparation and use in therapy and diagnosis of breast cancer.
2. Description of prior art
Tamoxifen is Z (1,2-diphenyl)-1-[4-(2-dimethylaminoethoxy)-phenyl]-1-butene of formula (1) ##STR2##
Its anti-estrogenic properties have led since 1971 to its clinical use in the treatment of malignant tumors, especially estrogen receptor-positive (hormone-dependent) breast cancer.
Tamoxifen has a relatively low affinity for the estrogen receptor (ER). Attempts have therefore been made to find tamoxifen derivatives having improved ER affinity. Changes have been made in virtually every part of the molecule. One derivative which at first seemed promising was the 4-hydroxy derivative of formulat (2) ##STR3## in which X=--OH. This compound was shown by in vitro tests to be a potent anti-estrogen, but unfortunately proved in vivo to be less effective than tamoxifen, owing to rapid glucuronidation of the hydroxyl group followed by excretion.
Several derivatives of tamoxifen are known which have other 4-position substituents, in which X is methoxy, methyl, fluoro or chloro. These compounds have been evaluated by K. E. Allen et al., British Journal of Pharmacology 71, 83-91 (1980). The methyl, chloro and fluoro derivatives were of particular interest as they are unlikely to be metabolised to the 4-hydroxy derivative and thence glucuronidated. An in vitro test of estrogen receptor affinity indicated that tamoxifen was approximately equiactive with its 4-methyl, fluoro- and chloro-derivatives. In vivo rat uterine weight tests indicated that these derivatives has lower anti-estrogenic activity than tamoxifen. Other tests indicated that the activity of the 4-methoxy derivative was about the same as tamoxifen.